GSK plc has disclosed that the United States Food and Drug Administration (FDA) has awarded Breakthrough Therapy Designation to Jemperli (dostarlimab) for patients dealing with locally advanced mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) rectal cancer. The Breakthrough Therapy Designation is designed to accelerate the development and approval processes for drugs that show potential in treating severe conditions and where early clinical studies suggest significant advancements over current therapies. This follows a Fast Track designation given to this subset of rectal cancer patients in January 2023.
Hesham Abdullah, GSK’s senior vice president and global head of oncology R&D, stated, “Today’s designation, founded on the unprecedented 100% clinical complete response rate achieved with dostarlimab so far, paves a potential path for transforming treatment for individuals with locally advanced dMMR/MSI-H rectal cancer, who often contend with long-term adverse quality-of-life outcomes. Our pivotal AZUR-1 trial continues to investigate dostarlimab for this patient group.”
The FDA’s Breakthrough Therapy Designation is supported by preliminary clinical data from an ongoing phase II collaborative study between GSK and Memorial Sloan Kettering Cancer Center. Results in the early stage of locally advanced dMMR rectal cancer reveal an exceptional 100% clinical complete response in all 42 patients who finished dostarlimab treatment, as assessed through diverse diagnostic methods including MRI, endoscopy, PET scan, and digital rectal exams. In the first cohort of 24 patients reviewed, a sustained response was observed over an average follow-up of 26.3 months. The safety profile for dostarlimab was consistent with its established safety ratings, with no grade 3 or worse adverse occurrences recorded. This trial is still assessing more patients, and GSK’s ongoing AZUR-1 phase II registration trial aims to corroborate these findings.
Currently, the standard treatment for individuals with locally advanced dMMR/MSI-H rectal cancer involves starting with chemoradiotherapy, followed by surgical excision of tumors and possibly affected intestines or tissue. While initially effective, this approach still sees nearly a third of patients eventually succumb to metastatic cancer. Furthermore, surgery and chemotherapy can have lasting adverse consequences on patients’ quality of life, affecting bodily functions, sexual health, and increasing risk of secondary health issues.
At present, dostarlimab is yet to be approved globally for frontline therapy targeting locally advanced dMMR/MSI-H rectal cancer.
Rectal cancer originates in the rectum, the terminal segment of the large intestines, and is a major component of colorectal cancer diagnoses, representing the third most common cancer type worldwide. In the U.S., around 46,220 new instances of rectal cancer are reported annually, with approximately 5-10% categorised as dMMR/MSI-H. This classification signals defects in DNA repair mechanisms within cells. The dMMR status serves as a biomarker predictive of response to immune checkpoint inhibitors like PD-1 therapy. Such anomalies are predominantly present in cancers of the endometrium, colorectal, and gastrointestinal tract but can manifest in other solid cancers too.
Jemperli acts as a PD-1 receptor blocker and constitutes the cornerstone of GSK’s research and development initiatives in immuno-oncology. Their ambitious clinical trial agenda examines Jemperli alone and in combination therapies across gynecologic, colorectal, and lung cancers, among other promising therapeutic areas.
In the U.S., Jemperli is approved alongside carboplatin and paclitaxel, subsequently used solo, to treat adult patients with primary advanced or recurrent endometrial cancer, covering MMRp/MSS and dMMR/MSI-H tumors. It is also sanctioned as a standalone for adults with dMMR advanced or recurrent endometrial cancer that has worsened post prior platinum-based therapies, where alternative treatments are unsuitable. Additionally, it holds approval for dMMR recurrent or advanced tumor care in adults, contingent on tumor response and prolonged impact, under the accelerated approval program. Further approval validation relies on confirming clinical advantages in ongoing studies.
The discovery of Jemperli can be attributed to AnaptysBio, Inc., later licensed to Tesaro, Inc., in an exclusive agreement signed in March 2014. Under these terms, GSK oversees the research, development, commercialization, and production of both Jemperli and cobolimab (GSK4069889), a TIM-3 antagonist.
Jemperli’s regulatory approval portfolio includes usage alongside carboplatin and paclitaxel for adults with advanced or recurrent endometrial cancer possessing dMMR/MSI-H characteristics and as a single therapy for adults with advanced recurrent endometrial cancer post other treatments.